1. Field of the Invention
The present invention relates to the use of solid arsenolite (As4O6), which is an angiogenesis inhibitor, and pharmaceutical composition containing the same. In particular, the present invention relates to newly discovered applications of As4O6, previously known as xe2x80x98Chonjisan(copyright)xe2x80x99, as treatment for angiogenesis and other associated diseases.
2. Description of the Background Art
Angiogenesis, the process of new vessel formation by the endothelial cells, is critical for the growth of tumors (Folkman J. Watson K, Ingber D, Hnahan D, Induction of angiogenesis during the transition from hyperplasia to neoplasia, Nature May 4, 1989; 339(6219); 58-61). And, its dominant feature is more obvious in many angiogenic disease like diabetic retinopathy, arthritis, hemangiomas and psoriasisis (Klagsbrun M and Folkman J in Peptide Growth Factors and Their Receptors II (eds Sporn M. B and Roberts, A. B.) 549-586 (Spring, Berlin, 1990)).
Neovascularization or invasion of vessels is usually observed in the corneas of patients suffering from Stevens-Johnson syndrome and similar diseases; ocular pemphigoid and similar diseases; corneal chemical injuries due to toxic chemicals i.e., alkalin, acid, detergent, or various kinds of solvents and volatile gases; trachoma; virus infection; phlyctenula keratitis; and patients who received corneal transplant, and patients who use contact lenses for long periods. Aqueous chamber, lenses or vitreous are originally transparent without vessel and if neovascularization occurs in these tissues, severe visual loss results in difficulty in every day life. Thus, a number of medicinal researches have been done to inhibit neovascularization.
Typically known angiogenesis inhibitors include protamine application (Taylor, S. et al., Nature, 297, 307, 1982), combination of heparine and cortizon (Folkman, J. et al., Science, 221, 71, 1983), predonisolone acetate (Robin, J. B., Arch, Opthalmol., 103, 284, 1985), sulfonated polysaccharide (Japanese laid-open No. 63-119500), Herbimycin A (Japanese patent laid-open No. 63-295509), Fumagillin (Japanese patent laid-open No. 1-279828) and interferon beta (U.S. Pat. No. 5,948,403). However, most of these are unsatisfactory because of insufficient activity, and especially, their adverse side effect on a human body has been a serious concern.
Arsenic is a well-known potent environmental carcinogen to cause skin and lung cancers. However, there have been used for treating psoriasis, syphilis, and rheumatism in the traditional oriental medicine. It was not until in 1970""s that Chinese discovered that arsenic trioxide (As2O3) remarkably cured acute promyelocytic leukemia (APL). Now, many researches are actively in process all over the world including the United States in connection with arsenic compounds"" functional groups and applications thereof (Zhang T D: Treatment of acute granulocytic leukemia with xe2x80x9cAi Ling No. 1xe2x80x9dxe2x80x94Clinical analysis and experimental research. Chin J Integrated Chin West Med 4:19, 1984) (Li Y S, Zhang T D, Li C H W, Zhao X L, Wei Z H R, Tan W, Li R L, Mao Y Y: Traditional Chinese and Western Medicine in the treatment of 27 patients with malignant lymphoma. Chin J Oncol 10:61, 1988) (Sun H D, Ma L, Hu X C, Zhang T D: Ai-Lin I treated 32 cases of acute promyelocytic leukemia. Chin J Integrated Chin West Med 12:170, 1992, Blood May 1, 1997; 89(9): 3354-60 Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Shen Z X, Chen G Q, Ni J H, Li X S, Xiong S M, Qiu Q Y, Zhu J, Tang W, Sun G L, Yang K Q, Chen Y, Zhou L, Fang Z W, Wang Y T, Ma J, Zhang T D, Chen S J, Chen Z, Wang Z Y).
In western countries, arsenic compounds were once used for treating syphilis, but now Melarsoprol, an organic arsenical used for treating trypanosomiasis, is the only arsenic compound in use. In vitro studies revealed that arsenic trioxide and Melarsoprol, is cytotoxic not only to APL cells but also to other types of leukemia cells by induction of apoptosis through the down regulation of Bcl-2 protein and/or activation of caspases (Blood Sep. 1, 1998;92 (5): 1497-504 Arsenic trioxide and melarsoprol induce programmed cell death in myeloid leukemia cell lines and function in PML and PML-RAR alpha independent manner. Wang Z G, Rivi R, Delva L, Konig A Scheinberg D A, Gambacorti-Passerini C, Gabrilove J L, Warrell R P Jr., Pandolfi P P, Blood Aug. 1, 1996;88 (3): 1052-61 In vitro studies on cellular and molecular mechanisms of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia: As2O3 induces NB4 cell apoptosis with down regulation of Bcl-2 expression and modulation of PML-RAR alpha/PML proteins. Chen G Q, Zhu J, Shi X G, Ni J H, Zhong H J, Si G Y, Jin X L, Tang W, Li X S, Xong S M, Shen Z X, Sun G L, Ma J, Zhang P, Zhang T D, Gazin C, Naoe T, Chen S J, Wang Z Y, Chen Z, Blood May 1, 1997; 89(9):3345-53 Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): I. As2O3 exerts dose-dependent dual effects on APL cells. Chen G Q, Shi X G, Tang W, Xiong S M, Zhu J, Cai X, Han Z G, Ni JH, Shi G Y, Jia P M, Liu M M, He K L, Niu C, Ma J, Zhang P, Zhang T D, Paul P, Naoe T, Kitamura K, Miller W, Waxam S, Wang Z Y, de The H, Chen S J, Chen Z, Br J Haematol September 1998; 102(4):1055-60 Arsenic induces apoptosis in B-cell leukaemic cell lines in vitro: activation of caspases and down-regulation of Bcl-2 protein. Akao Y, Mizoguchi H, Kojima S, Naoe T, Ohishi N, Yagi K, Blood Jul. 15, 1997;90(2): 562-70, Comparative activity of melarsoprol and arsenic trioxide in chronic B-cell leukemia lines., Konig A, Wrazel L, Warrell R P Jr., Rivi R, Pandolfi P P, Jakubowski A, Gabrilove J L).
Tetraarsenic oxide (solid As4O6) provides the starting material for arsenic trioxide and most other arsenic compounds, and is also utilized in pesticides and serves as a decolourizer in the manufacture of glass and as a preservative for hides. Therefore, the arsenolite was believed to be a toxic, carcinogenic chemical substance just like arsenic trioxide, and only its molecular structure has been the chemist""s main concern (Becker K. A., Plieth K., and Stranski I. N. The polymorphic modifications of arsenic trioxide. Prog. Inorg. Chem. 4, 1-72 (1962), Pupp C, Lao R. C., Murray J. J., pottie R. F., Equilibrium vapor concentrations of some polycyclic aromatic hydrocarbons, As4O6 and SeO2 and the collection efficiencies of these air pollutants. Atmospheric Environment Vol. 8, pp 915-925, 1974, Grzechnik A. Compressibility and vibrational modes in solid As4O6 Journal of Solid State Chemistry, 144 (2):416-422, May 1999).
In the meantime, the inventor discovered that As4O6, which was obtained from natural arsenic bearing ore, could be used as an anti-cancer agent, so he filed a patent application no. 1998-16486 with Korean Industrial Property Office, and in 1999, he was granted a patent on this same invention from Japanese Patent Office (Japanese Patent No. 3007627).
It was reported that arsenic trioxide, when taken through oral administration, caused serious side effect on gastrointestinal and liver (Shen Z X, Chen G Q, Ni J H, Li X S, Xiong S M, Qiu Q Y, Zhu J, Tang W, Sun G L, Yang K Q, Chen Y, Zhou L, Fang Z W, Wang Y T, Ma J, Zhang P, Zhang T D, Chen S J, Chen Z, Wang Z Y Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood May 1, 1997; 89(9): 3354-60). However, according to the inventor""s experiment, when oral administration of 100 mg/kg of arsenolite had been done for 28 days to the Sprague Dawley rat weighting around 200 g, only minor histological alterations was observed in kidney and no side affect on gastrointestinal and liver. Further, if 10 mg/kg and 1 mg/kg were applied, none of side effect was observed.
Accordingly, it is an object of the present invention to provide a novel angiogenesis inhibitor, arsenolite.
Another object of the present invention is to provide pharmaceutical compositions comprising the angiogenesis inhibitor described above.